1. Field of the Invention
The present invention relates to polyesters having predetermined monomeric sequence, i.e., they are exactly sequenced polyesters, and to methods of producing such exactly sequenced polyesters, and various articles produced from such exactly sequenced polyesters. More particularly, homogeneous hydroxyacid polymers having precisely defined sequences are produced according to the present invention.
2. Description of Related Art
Hydrolyzable polyesters such as those derived from polyhydroxyacids have many important applications as biodegradable polymers. The simplest poly(.alpha.-hydroxyacid), polyglycolic acid has been successfully used as a bioabsorbable implant material in surgical procedures. Likewise, polylactic acid has been used as a bioabsorbable implant material, either by itself or as a copolymer with glycolic acid. Other hydroxyacids, e.g., hydroxybutyric acid have also been utilized.
Polyglycolic acid is generally prepared from the cyclic diester of glycolic acid (glycolide) by ring opening addition polymerization in the presence of a catalyst. In a similar manner, polylactic acid can be obtained from the cyclic diester of lactic acid (lactide) by stannous octoate-catalyzed ring opening polymerization.
Copolymers of glycolic acid and lactic acid have been developed in an attempt to combine the characteristics of both compounds and extend the range of polymer properties and rates of hydrolysis. For example poly-L-lactic acid is hydrolyzed more slowly than polyglycolic acid and copolymers of the two acids can be made to hydrolyze at intermediate rates.
Poly(lactide-co-glycolide) polymers are heterogeneous, i.e., they are made up of a random sequence of lactate and glycolate dimers and it is statistically improbable any two chains will be identical. Ordinarily, properties of such copolymers are based, in part, upon the concentration of lactide and glycolide present in the starting reaction mixture. The formation of the copolymer is complicated by the fact that depending upon the catalyst used and other reaction conditions, the relative rates of reactivity of glycolide and lactide are different. For example, when equimolar amounts of glycolide and lactide are reacted, glycolide is initially more likely to combine with growing chains than is lactide. Consequently, the initial composition of the growing chain contains a predominance of glycolic acid units occasionally and randomly interspersed with short sequences of lactic acid units. As the reaction proceeds, the concentration of lactide contained in the mixture increases relative to glycolide and the ratio of glycolic acid units to lactic acid units forming the chain becomes more equal. As the reaction nears completion, most available glycolide has polymerized and the relative amount of lactide is high. Consequently, a larger number of lactic acid units are likely to come together and polymerize. Thus, the first portion of the copolymer chain is likely to contain a predominance of glycolic acid units, and the end portion of the chain is likely to contain a predominance of lactic acid units.
Random sequences generated by the synthesis of poly(lactide-co-glycolide) result in the formation of heterogeneous polymers, i.e., no two polymeric chains are likely to be identically duplicated. Consequently, the physical and chemical properties of such copolymers are difficult to predict or control with a high degree of precision. The ability to control synthesis of the precise compositional sequence of poly(lactide-co-glycolide) polymers would allow the physical and chemical properties of the polymeric products to be fixed to a high degree of certainty and allow the production of homogeneous polymers. For example, such control would allow polymers to be engineered to more precisely fit specific specifications such as degree of crystallinity and/or rates of hydrolysis.
It has been reported that pure polyglycolide is about 50% crystalline and pure poly-L-lactide is about 37% crystalline. See Gilding et al., Biodegradable Polymers for Use in Surgery, Polymer, 20:1459-1464 (1979). Gilding et al. also reported that poly(lactide-co-glycolide) polymers are amorphous between the compositional range of from 25 to 75 mole percent glycolide. This is so because of the amorphous character of the copolymer. For crystallinity to occur, extensive lengths of the chain need steric regularity which may be achieved with precise sequence control.
Precise control over the sequential arrangement of poly(lactide-co-glycolide) also would allow control over the rate of hydrolysis of the copolymer. The rate of hydrolysis of a glycolic acid-glycolic bond is greater than the rate of hydrolysis of lactic acid-glycolic acid bond which is greater than the rate of hydrolysis of a glycolic acid-lactic acid bond which is greater than the rate of hydrolysis of a lactic acid-lactic acid bond. Thus, in the copolymer segment: ##STR1## wherein glycolide is oriented to provide a hydroxy terminus on the left-most portion of the segment, i.e., HOCH.sub.2 CO.sub.2 CH.sub.2. . . COOH, the order of hydrolysis is 1&gt;4&gt;2&gt;3, i.e, 1 is fastest and 3 is slowest. Therefore, an engineered arrangement of sequential units would allow control over the rate at which a copolymer hydrolyzes.
U.S. Pat. No. 3,960,152 (the "'152 patent") describes an attempt to provide a copolymer having a controlled sequence of alternating units of lactic acid and polyglycolic acid. According to the '152 patent, lactic acid and glycolic acid are formed into a cyclic diester (3-methyl-1,4-dioxane-2,5-dione). When the cyclic diester is opened and added to a polymer chain, the lactic acid unit and glycolic acid unit are said to be adjacent in the polymer chain. However, there is no way to control the ring opening polymerization such that the ring opens at the same position every time. Thus, the ring opening and subsequent addition cannot be strictly uniform and the final product does not contain regularly alternating lactic acid units and glycolic acid units, i.e., the resulting polymer is not homogeneous.
Polydepsipeptides are copolymers of .alpha.-amino and .alpha.-hydroxycarboxylic acids with neighboring monomers linked either by an amide or an ester bond. Such copolymers are described as appropriate models for the conformational and optical properties of polypeptides and proteins. See, e.g., Goodman et al., Polydepsipeptides II: Synthesis and Preliminary Conformational Studies of an Alternating .alpha. Amino and .alpha. Hydroxy Acid Polymer, Israel Journal of Chemistry, 2:66-77 (1974) or Mathias et al., Polydepsipeptides.6. Synthesis of Sequential Polymers Containing Varying Ratios of L-Alanine and L-Lactic Acid, Macromolecules, 11 No. 3: 534-539 (May-June 1978). In these references, no more than two adjacent lactic acid residues were esterified with alanine to form polydepsipeptides for the purpose of allowing qualitative evaluation of the helix disrupting ability of two adjacent lactic acid residues.
Therefore, it would be advantageous to construct a polyester having a predetermined sequence of structural units by controlling the precise sequential arrangement of monomers in a polyester chain.